4U4S

Crystal structure of the GluA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and BPAM25 at 1.90 A resolution.

4U4S の概要

• エントリーDOI: 10.2210/pdb4u4s/pdb
• 関連するPDBエントリー: 3TDJ 4N07
• 分子名称: Glutamate receptor 2,Glutamate receptor 2, 4-ethyl-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine 1,1-dioxide, SULFATE ION, ... (9 entities in total)
• 機能のキーワード: ampa receptor ligand-binding domain, allosteric modulation, bpam25, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60516.07

構造登録者

Noerholm, A.B.,Deva, T.,Frydenvang, K.,Kastrup, J.S. (登録日: 2014-07-24, 公開日: 2014-11-19, 最終更新日: 2024-11-13)

主引用文献

Francotte, P.,Nrholm, A.B.,Deva, T.,Olsen, L.,Frydenvang, K.,Goffin, E.,Fraikin, P.,de Tullio, P.,Challal, S.,Thomas, J.Y.,Iop, F.,Louis, C.,Botez-Pop, I.,Lestage, P.,Danober, L.,Kastrup, J.S.,Pirotte, B.
Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides.
J.Med.Chem., 57:9539-9553, 2014

PubMed Abstract: Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.

PubMed: 25375781
DOI: 10.1021/jm501268r

実験手法

X-RAY DIFFRACTION (1.9 Å)